Musculoskeletal conditions represent a major source of pain, loss of function, and health care expenditure that costs Americans many billions, yearly. People with conditions causing chronic pain turn to integrative health practices to supplement other conventional medical treatment, or when their pain is resistant to or in an effort to avoid side effects of medications. However, scientific evidence of safety, efficacy and mechanisms of such practices are limited. European clinical research has provided evidence for safety and efficacy of the botanical Harpagophytum procumbens (H. procumbens or Devil's Claw) for many patients suffering from arthritis and chronic low back pain. The variability in the natural products, however, and lack of a well-defined biological signature necessitate additional exploratory studies with well-characterized products, so that subsequent clinical studies of appropriate methodological rigor can be conducted. The proposed project will use a well characterized product to assess a biological signature for a hypothesized mechanism of action. The R21 phase of the proposed project will address the following objectives: (1) further define the bioavailability and short term pharmacokinetics of the principal secondary metabolites of a well-characterized aqueous-ethanolic extract of H. procumbens in non-enteric and enteric formulations; (2) define the biological signature and hypothetical mechanism of action of the H. procumbens extract in patients with early stage inflammatory knee osteoarthritis over four week dosing; and, (3) develop protocol, data and safety monitoring plan and manual of operations/procedures and obtain all necessary regulatory approvals for the R33 phase. Following successful completion of the R21 phase, the following objectives will be addressed during the R33 phase: (1) confirm and extend assessment of the impact of the H. procumbens extract upon the biological signature of the above referenced systemic inflammatory biomarkers and biomarkers in synovial fluid of patients consuming either of two doses over twelve weeks; and, (2) evaluate the relationship between changes in systemic and local joint biomarker levels and clinical outcomes (pain, stiffness, functional difficulty). Completion of this study will ensure that future clinical trials can be conducted with the methodological rigor and outcome measures needed to appropriately evaluate the effectiveness of H. procumbens products.